This is a first submission to the NIH Pathway to Independence (K99/R00). Dr. Thompson is establishing herself as an independent investigator in the field of fetal programming, with a particular emphasis on maternal metabolic dysfunction and vascular risk in the offspring. This grant will be critical to achieve the following short and long-term objectives: 1) to acquire additional training in technical skills and scientific knowledg, particularly with respect to vascular function and signaling; 2) to develop an independent project using a model of gestational diabetes that will be serve as a foundation for an independent research program, and 3) to become an independently funded scientist at the forefront of cardiovascular programming. Dr. Thompson has assembled a multidisciplinary team, including mentor, co-mentor and consultants that will guide her career towards independence and assist with the completion of the research proposed in this application. By the end of the funding period of this K99/R00 award, it is expected that Dr. Thompson will have published several high- impact first and last author papers and successfully competed for subsequent NIH funding. The overall objective of the research plan is to explore the impact of metabolic dysfunction on cardiovascular risk throughout the lifespan. In the K99 phase, Dr. Thompson will utilize a dual transgenic mouse model whereby db/db mice are interbred with mice lacking the NADPH enzyme, Nox1, in order to isolate the role of Nox1 in the development of microvascular dysfunction in the context of the metabolic syndrome. Briefly, using gold-standard techniques such as myography and telemetry, cardiovascular function will be measured in db/db and lean mice with and without Nox1 deletion. This mentored project will furnish Dr. Thompson with conceptual and technical skills that will supplement her doctoral training in fetal physiology, and facilitate her independent investigation into the relationship between vascular disease and metabolic complications of pregnancy. In the R00 phase, Dr. Thompson will characterize the cardiometabolic phenotype of offspring born to Hetdb female mice, a novel model of GDM. With use of the same gold-standard techniques proposed for the K99 studies, Dr. Thompson will measure cardiovascular function in offspring born from hyperglycemic or normal pregnancy, with or without a secondary postnatal insult. In order to determine if programmed phenotypic changes trace to the intrauterine hyperglycemic environment, responses to inflammatory/redox stimuli will be measured in vascular cells isolated at term and at various postnatal time-points. This project will set the stage for future investigation into molecular mechanisms linking hyperglycemic pregnancy to abnormal vascular phenotype and allow Dr. Thompson to lay claim to this important field of study.